Available Technology
Permanently charged ion channel blockers as anti-inflammatory and asthma therapeutic agents
Technology:
Methods to reduce neurogenic inflammation
Markets Addressed
Whether applied with sodium channel blockers or calcium channel blockers, this approach can be used to treat multiple cutaneous or mucosal inflammatory conditions, including arthritis, colitis, gastritis, proctitis, conjuctivitus, urethritis, cystitis, rhinitis, asthma, and cough.
Drugs can be administered topically, by injection, inhalation, orally, and by other means.
Innovations and Advantages
Inflammation has two components; one mediated by immune cells and one mediated by the nervous system, which is termed neurogenic inflammation. Neurogenic inflammation results from an efferent (motor) action of peptidergic nociceptor sensory neurons in contrast to their afferent (sensory) function. The afferent, sensory function of nociceptors, results from transduction of external stimuli and conduction of action potential from the periphery to the CNS to cause pain and reflex withdrawal. The efferent, motor function of nociceptors results from the release of neuropeptides and other chemicals from their peripheral terminals when activated. This release is much like neurotransmitter release, and is mediated by depolarization of the nociceptor's peripheral ending by voltage-gated sodium channels leading to calcium influx through voltage-gated calcium channels, and exocytosis of vesicles (See Figure 1 below).
Release of neuropeptides can have multiple effects. It can lead to enhanced capillary permeability leading to edema, elicit pro-inflammatory reactions and recruitment of immune cells, cause vasodilation, and also propagate further afferent and efferent function by stimulating neighboring cells.
Neurogenic inflammation contributes to the peripheral inflammation elicited by tissue injury, autoimmune diseases, infection, exposure to irritants, and other stimuli in soft tissue, skin, the respiratory system, joints, the GI tract, brain, and other tissues and has been proposed to have an important role in arthritis, rhinitis, gastritis, and colitis. Recent data point to a central role of neurogenic inflammation in allergic airway inflammation and Crohn’s disease.
Drs. Bean and Woolf have tested and shown ways to reduce neurogenic inflammation. One way is to selectively block electrical excitation in nociceptors to prevent activation of peripheral terminals and subsequently the release of pro-inflammatory mediators (see Fig. 2). This can be done using sodium channel blocking agents such as local anesthetic agents, but the down side is that they are non-selective, have a relatively short duration of action, and will cause a block in all sensory and motor fibers. The invention is a targeted approach, using permanently charged sodium
channel blockers that do not normally permeate the membrane, but can enter cells via large pore ion channels such as TRPV1 and TRPA1. These channels are selectively localized on nociceptors, in preference to ottypes of neurons. Cellular permanently charged sodium channel blockers can be facilitated using an agonist that opens the large ionic pores, allowing the blocker to work intracellularly, eliminating sodium currents and thereby reducing neurogenic inflammation. To achieve this, a combination of a large pore ion channel agonist (such as lidocaine) and a permanently charged sodium channel blocker is required and exposure to the permanently charged sodium channel blocker alone will have no effect.
During active inflammation, however, many large pore ion channels are opened by multiple endogenous activators, and the permanently charged sodium channel blocker can be administered alone to treat neurogenic inflammation.
Both TRPA1 and TRPV1 are important for the perception of airway irritation and cough and promote asthmatic inflammation after inhaled allergen challenges, leading to cough, mucus production, bronchial hyperresponsiveness and immune cell infiltration. Blocking only one of these two TRP channels would leave the other available to induce reflexes and neurogenic inflammation in response to thermal, chemical or immune stimuli. A strategy that can block both the TRPA1- and TRPV1-mediated contributions to airways inflammation, and thereby eliminate the sensory neuronal component of asthma should be superior to TRPA1 or TRPV1 antagonists or neuropeptide antagonists. Targeting sodium channel blockers selectively into respiratory sensory fibers should achieve this. One aspect of the invention of Bean and Woolf is inhalation of permanently charged blockers for this purpose. For Crohns’ disease and other mucosal inflammatory diseases of the GIT, oral administration of the blocker should suffice since the hydrophilic drugs will not be absorbed.
A second way to reduce neurogenic inflammation is to block calcium entry through voltage-dependent calcium channels. Calcium entry is also important for the release of the neuropeptides/pro-inflammatory mediators. Membrane-impermeant versions of calcium channel-blocking drugs are normally inactive when applied outside the cell. However, Bean and Woolf have found that they can gain access into neurons by passing through large pore ion channels, similarly to that mentioned above.
Additional Information
Intellectual Property Status: Patent(s) pending
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Inventor(s):
Bean, Bruce P.
Woolf, Clifford
Categories:
For further information, please contact:
Michal Preminger, Director of Business Development
(617) 432-0920
Reference Harvard Case #3553